This project addresses the cellular signaling cascade in endocrine and neuroendocrine cells and the interactions between plasma membrane electrical events and receptor-mediated signaling. Current emphasis is on the characterization of action potential (AP)-driven calcium signaling in hypothalamic neurons (GT1 cells) and pituitary somatotrophs. Our analysis revealed that most GT1 cells exhibited spontaneous, extracellular calcium-dependent APs, which was initiated by a slow pacemaker depolarization. More hyperpolarized cells fired sharp APs with limited capacity to promote calcium influx, whereas more depolarized cells fired broad APs with enhanced capacity for calcium influx. Characterization of the inward currents in these cells revealed the presence of TTX-sensitive sodium and T- and L-type calcium components. The availability of sodium and T-type calcium channels was dependent on the baseline potential, which determined the activation/inactivation status of these channels. Whereas all three channels were involved in the generation of sharp APs, L-type channels were solely responsible for the spike depolarization in cells exhibiting broad APs. Activation of GnRH receptors led to biphasic changes in intracellular calcium concentration with an early, extracellular calcium-independent peak and a sustained, extracellular calcium-dependent phase. During the peak calcium response, electrical activity was abolished due to transient hyperpolarization. This was followed by sustained depolarization of cells and resumption of firing of increased frequency with a shift from sharp to broad APs. The transient hyperpolarization was caused by the initial spike in cytosolic calcium and was mediated by SK-type potassium channels, which were also operative during the subsequent depolarization phase. Agonist-induced depolarization and increased firing were independent of cytosolic calcium and were not mediated by inhibition of potassium current, but by facilitation of a voltage-insensitive calcium-conducting inward current. Store depletion by thapsigargin, a blocker of calcium pump expressed in endoplasmic reticulum, also activated this inward depolarizing current and increased the firing frequency. These results indicate that in both unstimulated and agonist-stimulated GT1 cells, membrane depolarization limits the participation of sodium and T-type channels in firing, but facilitates AP-driven calcium influx. Furthermore, the pattern of firing in GT1 neurons is coordinately regulated by calcium-controlled SK current and the store depletion-activated calcium current. Like GT1 neurons, somatotrophs also exhibited periods of spontaneous AP firing that generated high amplitude fluctuations in cytosolic calcium. In contrast to GT1 neurons, no information was available on the expression and coupling of calcium-mobilizing receptors and their role in the control of electrical activity. We have found the message and the specific binding sites for ET-A but not ET-B receptors in mixed pituitary cells and in highly purified somatotrophs. Activation of these receptors by ET-1 led to an increase in inositol trisphosphate production and the associated rise in cytoslic calcium and GH secretion. The calcium-mobilizing action of ET-1 lasted for 2-3 minutes and was followed by an inhibition of AP-driven calcium influx and GH secretion to below the basal levels. This inhibition was accompanied by the down regulation of adenylyl cyclase activity and by the stimulation of inward rectifier potassium current. In somatotrophs treated with pertussis toxin overnight, the ET-1-induced calcium-mobilizing phase was preserved, but was immediately followed by facilitated calcium influx and GH secretion. ET-1-induced inhibition of adenylyl cyclase activity was abolished in pertussis toxin-treated cells. These results indicate that the transient cross-coupling of calcium-mobilizing ET-A receptors to Gi/Go pathway in somatotrophs provides an effective mechanism to change the rhythm of calcium signaling and GH secretion during continuous agonist stimulation. Thus, in contrast to GnRH action in GT1 cells, where calcium-mobilization phase was accompanied with facilitated voltage-gated calcium influx, these two phases in ET-stimulated somatotrophs were transiently dissociated.